Fatty liver, also known as fatty liver disease (FLD) or hepatic steatosis, is a reversible condition in which large vacuoles of triglyceride fat accumulate in liver cells via the process of steatosis (i.e., abnormal retention of lipids within a cell). Despite having multiple causes, fatty liver is most commonly associated with excessive alcohol consumption and obesity. FLD associated with other diseases that influence fat metabolism is referred to as “non-alcoholic” FLD or “NAFLD.”
Fatty change represents the intracytoplasmatic accumulation of triglycerides (neutral fats). At the onset of FLD, the hepatocytes present small fat vacuoles (liposomes) around the nucleus (microvesicular fatty change). In late stages of FLD, the size of the vacuoles increase and vacuoles coalesce to produce irreversible fatty cysts or lesions. Liver disease with extensive inflammation and a high degree of steatosis often progresses to more severe forms of the disease.
Non-alcoholic steatohepatitis (NASH) is an extreme and progressive form of NAFLD that is not linked to alcohol consumption and is further accompanied by inflammation (hepatitis). NASH is accompanied by ballooning degeneration of hepatocytes (also referred to herein as “hepatocyte ballooning”), which refers to the increase in size (i.e., ballooning) of cells during this process that is considered to be a form of apoptosis. Ballooned cells are typically two to three times the size of adjacent hepatocytes and characterized by a wispy cleared cytoplasm on H&E stained sections. Liver cell death and the inflammatory response lead to activation of stellate cells, which play a pivotal role in hepatic fibrosis. Further disease progression leads to cirrhosis and hepatocellular carcinoma (HCC), resulting in liver failure and, ultimately, death.
For patients suffering from early stages of NASH, lifestyle intervention, such as significant weight reduction, may slow or even reverse the process of steatosis. However, for patients with advanced NASH, there are no currently available therapies. For example, a recent clinical study of cenicriviroc for the treatment of advanced NASH failed to meet its primary endpoint of improving inflammation and liver damage after a year of treatment. Given the severity of FLD and NASH and unmet clinical need, an effective therapeutic treatment is urgently needed.